Abstract
BACKGROUND: The combination of task-oriented training and vagus nerve stimulation has recently received US Food and Drug Administration approval to improve upper limb recovery in individuals with chronic stroke. Although conventional vagus nerve stimulation systems have a long track record of solid performance, they have been minimally redesigned since their entry onto the market in 1997 and are ripe for improvement. To leverage this opportunity, we developed a miniaturized system tailored specifically for closed-loop vagus nerve stimulation therapy (CLV). The system is ≈50-fold smaller, simplifies implantation, and interacts with sensors for closed-loop triggering during personalized rehabilitation sessions. Here, we performed a randomized, sham-controlled trial to evaluate the safety, feasibility, and initial effectiveness of this system. METHODS: In the primary study, conducted from September 2021 to January 2024 in Dallas, TX, 19 participants with ischemic stroke that occurred at least 1 year prior and residual upper limb deficits were implanted. Participants entered the double-blinded phase, during which they were randomized to receive 18 sessions of individualized, progressive rehabilitation with active CLV or sham stimulation followed by an additional 18 sessions of rehabilitation with active CLV, regardless of prior group assignment. After completion of this primary study, a subset of participants entered an exploratory extension during which they received up to 100 additional sessions of self-paced CLV at home. RESULTS: Analysis of the primary outcome showed a nature and rate of adverse events similar to or below conventional vagus nerve stimulation devices. Heart rate and blood pressure were unaffected by CLV. Secondary functional outcomes demonstrated that, after CLV therapy in the randomized controlled trial phase, participants exhibited significant improvements in the upper extremity Fugl-Meyer score of 5.3±0.7 points over baseline (P<0.001). Additional therapy in the exploratory extension resulted in improvements of 10.9±1.3 points in upper extremity Fugl-Meyer score (P<0.001). CONCLUSIONS: These findings indicate that this miniaturized CLV system merits evaluation in a larger study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04534556.